Subscribe to RSS
DOI: 10.1055/s-0031-1296409
Cytotoxicity of 1-Aryl-3-buthylamino-1-propanone Hydrochlorides against Jurkat and L6 Cells
Publication History
Publication Date:
13 December 2011 (online)
![](https://www.thieme-connect.de/media/amf/200907/lookinside/thumbnails/10.1055-s-0031-1296409-1.jpg)
Abstract
1-Aryl-3-buthylamino-1-propanone hydrochloride type mono Mannich bases were synthesized and their cytotoxicity was tested against transformed human T-lymphocytes (Jurkat cells) and rat skeletal muscle derived myoblasts (L6 cells). Aryl part was changed as phenyl in 1, 4-methylphenyl in 2, 4-chlorophenyl in 3, 4-fluorophenyl in 4, 4-bromophenyl in 5, 4-hydroxyphenyl in 6, 2-acethylthiophene in 7. Of the compounds synthesized, 2, 5, 6, and 7 are reported for the first time. Compounds 1–7 had 3.16, 3.13, 3.35, 2.87, 4.17, 2.60, and 3.04 times higher cytotoxic potency than the reference compound 5-fluorouracil (CAS 51-21-8) against Jurkat cells, respectively. Compounds 1, 3, 4, 5, 6, and 7 had 1.22, 1.46, 1.59, 2.18, 1.24, and 1.45 times higher cytotoxic potency than the reference compound 5-fluorouracil against L6 cells, respectively. Among the compounds tested, only compound 5 had almost equal cytotoxic potency with the reference compound melphalan (CAS 148-82-3) against Jurkat and L6 cells. All compounds synthesized showed higher cytotoxic activity against Jurkat cells compared with L6 cells. Specifically, compounds 1−7 had 2.05, 2.68, 1.82, 1.43, 1.51, 1.66, and 1.66 times higher cytotoxicity against Jurkat cells compared with L6 cells. In Jurkat cells, there was a significant negative correlation between Log P and IC50 values (correlation coefficient: −0.955, p = 0.03), which actually means a positive correlation between the Log P and the cytotoxic activity of the compounds. These results suggest that the most potent compound 5 (a 4-bromo derivative) against both cell lines may serve as a model compound to develop new cytotoxic agents for further studies.
-
References
- 1 Dimmock JR, Kumar P. Anticancer and cytotoxic properties of Mannich bases. Curr Med Chem. 1997; 4: 1-22
- 2 Mete E, Gul HI, Kazaz C. Synthesis of 1-aryl-3-phenethylamino-1-propanone hydrochlorides as possible potent cytotoxic agents. Molecules. 2007; 12: 2579-88
- 3 Erciyas E, Erkaleli HI, Cosar G. Antimicrobial evaluation of some styryl ketone derivatives and related thiol adducts. J Pharm Sci. 1994; 83: 545-8
- 4 Gul HI, Sahin F, Gul M, Ozturk S, Yerdelen KO. Evaluation of antimicrobial activities of several mannich bases and their derivatives. Arch Pharm (Weinheim). 2005; 338: 335-8
- 5 Gul HI, Ojanen T, Hanninen O. Antifungal evaluation of some bis Mannich bases derived from acetophenone and their corresponding piperidinols and stability studies. Biol Pharm Bull. 2002; 25: 1307-10
- 6 Gul HI, Denizci AA, Erciyas E. Antimicrobial evaluation of some Mannich bases of acetophenones and their representative quaternary derivatives. Arzneimittelforschung. 2002; 52: 773-7
- 7 Gul HI, Ojanen T, Vepsalainen J, Gul M, Erciyas E, Hanninen O. Antifungal activity of some mono, bis and quaternary Mannich bases derived from acetophenone. Arzneimittelforschung. 2001; 51: 72-5
- 8 Vashishtha SC, Dimmock JR, Manavathu EK. Antifungal activity of some quaternary ammonium salts of 4-(2-arylvinyl)-3-(3-aryl-2-propenoyl)-1-ethyl-4-piperidinols and related compounds. Pharmazie. 1998; 53: 499-500
- 9 Medic-Saric M, Maysinger D, Movrin M, Dvorzak I. Antibacterial and antifungal activities of nitroxoline Mannich bases. Chemotherapy. 1980; 26: 263-7
- 10 Manavathu EK, Vashishtha SC, Alangaden GJ, Dimmock JR. In vitro antifungal activity of some Mannich bases of conjugated styryl ketones. Can J Microbiol. 1998; 44: 74-9
- 11 Dimmock JR, Kumar P, Manavathu EK, Obedeanu N, Grewal J. Activity of some Mannich bases of conjugated styryl ketones against Candida albicans. Pharmazie. 1994; 49: 909-12
- 12 Gul HI, Vepsalainen J, Gul M, Erciyas E, Hanninen O. Cytotoxic activities of mono and bis Mannich bases derived from acetophenone against Renca and Jurkat cells. Pharm Acta Helv. 2000; 74: 393-8
- 13 Gul HI, Gul M, Erciyas E. Syntheses and stability studies of some Mannich bases of acetophenones and evaluation of their cytotoxicity against Jurkat cells. Arzneimittelforschung. 2002; 52: 628-35
- 14 Gul M, Gul HI, Vepsalainen J, Erciyas E, Hänninen O. Effect of acetophenone derived Mannich bases on cellular glutathione level in Jurkat cells: a possible mechanism of action. Arzneimittelforschung. 2001; 51: 679-82
- 15 Gul HI, Gul M, Hanninen O. Cytotoxic activities of some mono and bis Mannich bases derived from acetophenone in brine shrimp bioassay. Arzneimittelforschung. 2002; 52: 840-3
- 16 Gul HI, Gul M, Vepsalainen J, Erciyas E, Hanninen O. Cytotoxicity of some azines of acetophenone derived mono-Mannich bases against Jurkat cells. Biol Pharm Bull. 2003; 26: 631-7
- 17 Gul M, Gul HI, Das U, Hanninen O. Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxopropyl)-methylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their alkylating ability towards cellular glutathione in human leukemic T cells. Arzneimittelforschung. 2005; 55: 332-7
- 18 Gul M, Atalay M, Gul HI, Nakao C, Lappalainen J, Hanninen O. The effects of some Mannich bases on heat shock proteins HSC70 and GRP75, and thioredoxin and glutaredoxin levels in Jurkat cells. Toxicol in Vitro. 2005; 19: 573-80
- 19 Gul HI, Das U, Pandit B, Li PK. Evaluation of the cytotoxicity of some mono-mannich bases and their corresponding azine derivatives against and rogen-independent prostate cancer cells. Arzneimittelforschung. 2006; 56: 850-4
- 20 Gul HI, Yerdelen KO, Gul M, Das U, Pandit B, Li PK et al. Synthesis of 4’-hydroxy-3’-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines. Arch Pharm (Weinheim). 2007; 340: 195-201
- 21 Gul HI, Yerdelen KO, Das U, Gul M, Pandit B, Li PK et al. Synthesis and Cytotoxicity of Novel 3-Aryl-1-(3’-dibenzyla-minomethyl-4’-hydroxyphenyl)-propenones and Related Compounds. Chem Pharm Bull (Tokyo). 2008; 56: 1675-81
- 22 Gul HI, Cizmecioglu M, Zencir S, Gul M, Canturk P, Atalay M, et al. Cytotoxic activity of 4’-hydroxychalcone derivatives against Jurkat cells and their effects on mammalian DNA topoisomerase I. J Enzyme Inhib Med Chem. (in press). DOI: 10.1080/147563608023912.
- 23 Canturk P, Kucukoglu K, Topcu Z, Gul M, Gul HI. Effect of Some Bis Mannich Bases and Corresponding Piperidinols on DNA Topoisomerase I. Arzneimittelforschung. 2008; 58: 686-91
- 24 Gul HI, Gul M, Erciyas E. Toxicity of some bis Mannich bases and corresponding piperidinols in the brine shrimp (Artemia salina) bioassay. J Appl Toxicol. 2003; 23: 53-7
- 25 Gul M, Gul HI, Hanninen O. Effects of Mannich bases on cellular glutathione and related enzymes of Jurkat cells in culture conditions. Toxicolin Vitro. 2002; 16: 107-12
- 26 Vashishtha SC, Allen TM, Halleran S, Szydlowski J, Santos CL, De Clercq E et al. Cytotoxic and anticancer properties of some 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinols and related compounds. Pharmazie. 2001; 56: 390-93
- 27 Vashishtha SC, Nazarali AJ, Dimmock JR. Application of fluorescence microscopy to measure apoptosis in Jurkat T cells after treatment with a new investigational anticancer agent (N.C.1213). Cell Mol Neurobiol. 1998; 18: 437-45
- 28 Chen HT, Jing YK, Ji ZZ, Zhang BF. [Synthesis and antiinflammatory and anticancer activities of 2-(E)-(un)substituted benzylidene cyclopentanones and their Mannich base hydro chlorides]. Yao Xue Xue Bao. 1991; 26: 183-92
- 29 Dimmock JR, Vashishtha SC, Patil SA, Udupa N, Dinesh SB, Devi PU et al. Cytotoxic and anticancer activities of some 1-aryl-2-dimethylaminomethyl-2-propen-1-one hydrochlorides. Pharmazie. 1998; 53: 702-6
- 30 Rubat C, Coudert P, Albuisson E, Bastide J, Couquelet J, Tronche P. Synthesis of Mannich bases of arylidenepyridazinones as analgesic agents. J Pharm Sci. 1992; 81: 1084-7
- 31 Suleyman H, Gul HI, Gul M, Alkan M, Gocer F. Anti-inflammatory activity of bis(3-aryl-3-oxo-propyl)methylamine hydrochloride in rat. Biol Pharm Bull. 2007; 30: 63-7
- 32 Suleyman H, Gul HI, Asoglu M. Antiinflammatory activity of 3-benzoyl-1-methyl-4-phenyl-4-piperidinol hydrochloride. Pharmacol Res. 2003; 47: 471-5
- 33 Gul HI, Suleyman H, Gul M Evaluation of the anti-inflammatory activity of N,N’-Bis(3-dimethylamino-1-phenyl-propylidene) hydrazine dihydrochloride. Pharmaceutical Biology. (in press).
- 34 Dimmock JR, Jonnalagadda SS, Phillips OA, Erciyas E, Shyam K, Semple HA. Anticonvulsant properties of some Mannich bases of conjugated arylidene ketones. J Pharm Sci. 1992; 81: 436-40
- 35 Borenstein MR, Doukas PH. Anticonvulsant activity of in-danylspirosuccinimide Mannich bases. J Pharm Sci. 1987; 76: 300-2
- 36 Gul HI, Calis U, Vepsalainen J. Synthesis and evaluation of anticonvulsant activities of some bis-Mannich bases and corresponding piperidinols. Arzneimittelforschung. 2002; 52: 863-9
- 37 Gul HI, Calis U, Vepsalainen J. Synthesis of some mono-Mannich bases and corresponding azine derivatives and evaluation of their anticonvulsant activity. Arzneimittelforschung. 2004; 54: 359-64
- 38 Gul HI, Calls U, Ozturk Z, Tutar E, Calikiran L. Evaluation of anticonvulsant activities of bis(3-aryl-3-oxo-propyl)-ethylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinol hydrochlorides. Arzneimittelforschung. 2007; 57: 133-6
- 39 Pati HN, Das U, Sharma RK, Dimmock JR. Cytotoxic thiol alkylators. Mini Rev Med Chem. 2007; 7: 131-139
- 40 Hansen MB, Nielsen SE, Berg K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods. 1989; 119: 203-10
- 41 Freshny RI. Culture of Animal Cells: A Manual of Basic Technique. New York: John & Wiley Sons, Inc; 2005
- 42 Plati JT, Schmidt RA, Wenner W. 1,3,4-Trisubstituted piperidine derivatives from Mannich bases. J Org Chem. 1949; 14: 873-8
- 43 Wilkerson WW inventor Du Pont Merck Pharmaceutical Company, Wilmington, Del., assignee. Benzylketone phospholipase A2 inhibitors. US patent 5,075,339. 1991 Dec. 24, 1991.